Monocyte-Derived Dendritic Cells as Antigen-Presenting Cells in T-Cell Proliferation and Cytokine Production

2019 ◽  
pp. 131-141
Author(s):  
Sun-Sang J. Sung
Keyword(s):  
Cell Proliferation ◽  
Dendritic Cells ◽  
T Cell ◽  
Cytokine Production ◽  
Antigen Presenting Cells ◽  
T Cell Proliferation ◽  
Antigen Presenting

IFN-α Suppresses Myeloid Cytokine Production, Impairing IL-12 Production and the Ability to Support T-Cell Proliferation

2020 ◽  
Vol 222 (1) ◽  
pp. 148-157
Author(s):  
Aman Mehrotra ◽  
June Ann D’Angelo ◽  
Amanda Romney-Vanterpool ◽  
Tom Chu ◽  
Antonio Bertoletti ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Chronic Hepatitis ◽  
T Cell ◽  
Hepatitis B ◽  
Chronic Hepatitis B ◽  
Cytokine Production ◽  
Antigen Presenting Cells ◽  
T Cell Proliferation ◽  
Hla Dr ◽  
Antigen Presenting

Abstract Background Interferon-α (IFN-α) can suppress production of T-cell polarizing cytokines or induce inhibitory antigen-presenting cells that suppress T-cell activation. Previous studies showed that IFN-α therapy fails to boost virus-specific T-cell immunity in patients with chronic hepatitis B virus infection. Our aim was to determine whether IFN-α exposure alters human antigen-presenting cell function in vivo. Methods We investigated the immunomodulatory effects using peripheral blood mononuclear cells from healthy donors exposed to IFN-α and chronic hepatitis B (CHB) patients starting IFN-α therapy. Results IFN-α increased HLA-DR, CD80, CD86, and PD-L1 expression on healthy donor monocytes. In contrast to the activated phenotype, IFN-α inhibited Toll-like receptor-induced cytokine production and monocyte-induced T-cell proliferation. In CHB patients, peg-IFN treatment induced an interferon-stimulated gene signature in monocytes and increased HLA-DR, CD80, CD86, and PD-L1 expression. As early as 3 days after CHB patients started treatment, IFN-α inhibited monocyte cytokine production and T-cell stimulation ex vivo. IFN-α-mediated inhibition of IL-12 production, rather than inhibitory receptor expression, was responsible for inhibition of T-cell proliferation. Addition of IL-12 restored T-cell proliferation to baseline levels. Conclusions Understanding how professional antigen-presenting cells respond to immunomodulation is important for both new innate and adaptive-targeted immunotherapies. Clinical Trials Registration NCT00962871.

scholarly journals Inhibition of Allogeneic T Cell Proliferation by Indoleamine 2,3-Dioxygenase–expressing Dendritic Cells

2002 ◽  
Vol 196 (4) ◽  
pp. 447-457 ◽  
Author(s):  
Peter Terness ◽  
Thomas M. Bauer ◽  
Lars Röse ◽  
Christoph Dufter ◽  
Andrea Watzlik ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
Cell Death ◽  
Dendritic Cells ◽  
T Cell ◽  
Antigen Presenting Cells ◽  
T Cell Proliferation ◽  
Inhibition Of Proliferation ◽  
Indoleamine 2,3 Dioxygenase ◽  
Antigen Presenting

Indoleamine 2,3-dioxygenase (IDO), an enzyme involved in the catabolism of tryptophan, is expressed in certain cells and tissues, particularly in antigen-presenting cells of lymphoid organs and in the placenta. It was shown that IDO prevents rejection of the fetus during pregnancy, probably by inhibiting alloreactive T cells, and it was suggested that IDO-expression in antigen-presenting cells may control autoreactive immune responses. Degradation of tryptophan, an essential amino acid required for cell proliferation, was reported to be the mechanism of IDO-induced T cell suppression. Because we wanted to study the action of IDO-expressing dendritic cells (DCs) on allogeneic T cells, the human IDO gene was inserted into an adenoviral vector and expressed in DCs. Transgenic DCs decreased the concentration of tryptophan, increased the concentration of kynurenine, the main tryptophan metabolite, and suppressed allogeneic T cell proliferation in vitro. Kynurenine, 3-hydroxykynurenine, and 3-hydroxyanthranilic acid, but no other IDO-induced tryptophan metabolites, suppressed the T cell response, the suppressive effects being additive. T cells, once stopped in their proliferation, could not be restimulated. Inhibition of proliferation was likely due to T cell death because suppressive tryptophan catabolites exerted a cytotoxic action on CD3+ cells. This action preferentially affected activated T cells and increased gradually with exposure time. In addition to T cells, B and natural killer (NK) cells were also killed, whereas DCs were not affected. Our findings shed light on suppressive mechanisms mediated by DCs and provide an explanation for important biological processes in which IDO activity apparently is increased, such as protection of the fetus from rejection during pregnancy and possibly T cell death in HIV-infected patients.

scholarly journals CD26 Mediates Dissociation of Tollip and IRAK-1 from Caveolin-1 and Induces Upregulation of CD86 on Antigen-Presenting Cells

2005 ◽  
Vol 25 (17) ◽  
pp. 7743-7757 ◽  
Author(s):  
Kei Ohnuma ◽  
Tadanori Yamochi ◽  
Masahiko Uchiyama ◽  
Kunika Nishibashi ◽  
Satoshi Iwata ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Molecular Mechanisms ◽  
Interleukin 1 ◽  
Costimulatory Molecule ◽  
Antigen Presenting Cells ◽  
T Cell Proliferation ◽  
Caveolin 1 ◽  
Extracellular Region ◽  
Antigen Presenting

ABSTRACT CD26 is a T-cell costimulatory molecule with dipeptidyl peptidase IV enzyme activity in its extracellular region. We have previously reported that the addition of recombinant soluble CD26 resulted in enhanced proliferation of human T lymphocytes induced by the recall antigen tetanus toxoid (TT) via upregulation of CD86 on monocytes and that caveolin-1 was a binding protein of CD26, and the CD26-caveolin-1 interaction resulted in caveolin-1 phosphorylation (p-cav-1) as well as TT-mediated T-cell proliferation. However, the mechanism involved in this immune enhancement has not yet been elucidated. In the present work, we perform experiments to identify the molecular mechanisms by which p-cav-1 leads directly to the upregulation of CD86. Through proteomic analysis, we identify Tollip (Toll-interacting protein) and IRAK-1 (interleukin-1 receptor-associated serine/threonine kinase 1) as caveolin-1-interacting proteins in monocytes. We also demonstrate that following stimulation by exogenous CD26, Tollip and IRAK-1 dissociate from caveolin-1, and IRAK-1 is then phosphorylated in the cytosol, leading to the upregulation of CD86 via activation of NF-κB. Binding of CD26 to caveolin-1 therefore regulates signaling pathways in antigen-presenting cells to induce antigen-specific T-cell proliferation.

Adhesion of human T cells to antigen-presenting cells through SIRPβ2-CD47 interaction costimulates T-cell proliferation

Blood ◽  
2005 ◽  
Vol 105 (6) ◽  
pp. 2421-2427 ◽  
Author(s):  
Laura Piccio ◽  
William Vermi ◽  
Kent S. Boles ◽  
Anja Fuchs ◽  
Carey A. Strader ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Antigen Presenting Cells ◽  
Cell Types ◽  
Orphan Receptor ◽  
T Cell Proliferation ◽  
Central Nervous Systems ◽  
And Function ◽  
Antigen Presenting

AbstractSignal-regulatory proteins (SIRPs) are transmembrane glycoproteins belonging to the immunoglobulin (Ig) superfamily that are expressed in the immune and central nervous systems. SIRPα binds CD47 and inhibits the function of macrophages, dendritic cells, and granulocytes, whereas SIRPβ1 is an orphan receptor that activates the same cell types. A recently identified third member of the SIRP family, SIRPβ2, is as yet uncharacterized in terms of expression, specificity, and function. Here, we show that SIRPβ2 is expressed on T cells and activated natural killer (NK) cells and, like SIRPα, binds CD47, mediating cell-cell adhesion. Consequently, engagement of SIRPβ2 on T cells by CD47 on antigen-presenting cells results in enhanced antigen-specific T-cell proliferation.

scholarly journals Expression and functional significance of an additional ligand for CTLA-4

1993 ◽  
Vol 90 (23) ◽  
pp. 11054-11058 ◽  
Author(s):  
D J Lenschow ◽  
G H Su ◽  
L A Zuckerman ◽  
N Nabavi ◽  
C L Jellis ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
B Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Costimulatory Molecule ◽  
T Cell Proliferation ◽  
Antigen Presenting

Effective T-cell activation requires antigen/major histocompatibility complex engagement by the T-cell receptor complex in concert with one or more costimulatory molecules. Recent studies have suggested that the B7 molecule, expressed on most antigen presenting cells, functions as a costimulatory molecule through its interaction with CD28 on T cells. Blocking the CD28/B7 interaction with CTLA4Ig inhibits T-cell activation in vitro and induces unresponsiveness. We demonstrate that another molecule(s), termed B7-2, is expressed constitutively on dendritic cells, is differentially regulated on B cells, and costimulates naive T cells responding to alloantigen. B7-2 is up-regulated by lipopolysaccharide in < 6 hr and is maximally expressed on the majority of B cells by 24 hr. In contrast, B7 is detected only on a subset of activated B cells late (48 hr) after stimulation. In addition, Con A directly induces B7-2 but not B7 expression on B cells. Finally, although both anti-B7 monoclonal antibodies and CTLA4Ig blocked T-cell proliferation to antigen-expressing B7 transfectants, only CTLA4Ig had any significant inhibitory effect on T-cell proliferation to antigens expressed on natural antigen presenting cells, such as dendritic cells. Thus, B7 is not the only costimulatory molecule capable of initiating T-cell responses since a second ligand, B7-2, can provide a necessary second signal for T-cell activation.

CD40-Licensing Of Human Dendritic Cells Further Matures Tnfa-Treated Dcs But Does Not Mediate Resistance Against Inhibition Of T-Cell Proliferation By TREG

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4726-4726
Author(s):  
Matthias Eyrich ◽  
Johannes Rachor ◽  
Marissa Blume ◽  
Isabelle Becker ◽  
Anne Stumpf ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Dendritic Cells ◽  
T Cell ◽  
Cancer Immunotherapy ◽  
Cytokine Production ◽  
T Cell Proliferation ◽  
Autologous Tumor ◽  
T Helper ◽  
Cell Proliferation Inhibition ◽  
T Cell Priming

Vaccination with cytokine-matured dendritic cells (DCs), loaded with autologous tumor lysate, represents a promising strategy in cancer immunotherapy, however, in clinical trials vaccination with this kind of DCs has shown only limited efficacy so far. In animal experiments, CD40-licensing of DCs conveys resistance to tumor-induced immunosuppression including immunomodulation of regulatory T cells (Tregs). DCs were generated by differentiation of monocytes for 7 days with GM-CSF/IL-4 followed by 48h maturation with TFNα/IL-1ß ± CD40L. Then, DC were analyzed with respect to phenotype, cytokine production, and T-cell stimulatory capacity. CD40-licensed DCs showed higher expression of CD86 (MFI 3074±630 vs. 2433±359 with vs. without CD40L, respectively, p<.05) and a trend towards higher CD80, CD83 expression. Coculture of DCs with Tregs during maturation led to a reduction of costimulatory molecules, presumably by transendocytosis of Tregs. This phenomenon could be partially abrogated by CD40-licensing. TNFα/IL1ß-matured DCs produced significant amounts of IL-6, IL-8, TNFα, and IL-1ß. CD40-licensing did further increase cytokine production, however, no IL-12 could be detected. In contrast to murine DCs, a second round of LPS-stimulation after TNFα/IL1ß could not trigger IL-12 production. Control DCs matured with LPS/IFNγ showed up to 16% IL-12+ DCs. Using Melan-A as a model tumor antigen, priming capacity of CD40-licensed DCs to induce Melan-A specific CD8+ CTLs was slightly but not significantly improved compared to nonlicensed DCs, as demonstrated by somewhat higher frequencies of Melan-A multimer+ and TNFα+IFNγ+ CTLs after 11 days of culture with CD40-licensed DCs and rechallenge, respectively. Again, T-cell priming was best with control DCs matured with LPS/IFNγ. In contrast to T-cell priming, CD40-licensed DCs did not show any improved capacity to stimulate CD4+ T-helper cell proliferation. Furthermore, in a classcial MLR-suppression assay Tregs inhibited CD4+ T-helper proliferation by approx. 40%, this suppression was not alleviated by CD40-licensing of DCs. Interestingly, Treg proliferation in combined MLR-assays was increased in all experimental settings. Treg-suppression of CD4+ T-helper proliferation as well as the increased Treg-proliferation in the combined MLR-assays could not be prevented by the lysosomal inhibitor Bafilomycin A. This suggests, that other mechanisms than transendocytosis of costimulatory molcules by Tregs mediate these effects. In summary, these data show that CD40-licensing is a feasible tool to improve maturity of cytokine-treated DCs. However, CD40-licensing cannot induce IL-12 production in human DCs without TLR-stimulation and was not able to confer resistance against Treg-mediated T-cell proliferation inhibition. Thus, in order to strengthen DCs for cancer immunotherapy, CD40-licensing should be further investigated in combination with TLR-triggering DC-maturation cocktails. Disclosures: No relevant conflicts of interest to declare.

scholarly journals CTLA-4 expressed by human dendritic cells modulates thei cytokine secretion and induction of T cell proliferation

2011 ◽  
Vol 84 (1) ◽  
Author(s):  
S. Laurent ◽  
P. Carrega ◽  
D. Saverino ◽  
P. Piccioli ◽  
M. Camoriamo ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Dendritic Cells ◽  
T Cell ◽  
Cytokine Production ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
T Cell Proliferation ◽  
Human Monocytes ◽  
Enhanced Secretion ◽  
Human Dendritic Cells

<p>CTLA-4 is the major nefative regulator of T cell response. We have analyzed the expression of CTLA-4 in human monocytes and monocyte-derived DCs and the effects of its engagement on cytokine production and T cell stimulatory activity by mature DCs (mDCs). We found the CTLA-4 was highly expressed on freshly isolated monocytes, then down-modulated on the immature DCs (iDCs) and upregulated on mDCs. Treatment of mDCS with an agonistic anti-CTLA-4 m Ab enhanced secretion of IL-10 but reduced secretion of IL-8 and IL-12, as well as autologous CD4* T-cell proliferation in response to simulation with PPD recall antigenloaded-DCs. Neutralization of IL-10 with an anti-IL-10 antibody partially restored the ability of anti-CTLA-4-treated mDCs to stimulate T cell proliferation in response to PPD. Our data provide the first evidence that CTLA-4 receptor is expressed by human mDCs and exerts immune modulatory effects in these cells.</p>

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